Project 1 Abstract Cancer represents a major health disparity in American, as both incidence of and mortality related to cancer are significantly higher in African Americans than in Caucasians. In addition, the Washington, D.C. area has one of the highest incidence rates of cancer in United States. To address these cancer health disparities in the greater Washington D.C. metropolitan area, it is essential to combine the strengths of a leading cancer center and a leading minority-serving institution. Howard University College of Dentistry (HUCD) is the only minority-oriented dental school in the Baltimore-Washington area, while Johns Hopkins Cancer Center is one of the world's leaders in translational cancer research. The overall objectives for this project are to establish collaborative research, training and career development between Howard University and the Johns Hopkins Cancer Center. Dr. T.-C. Wu, an experienced clinical investigator with an active translational molecular immunology laboratory at Johns Hopkins University, will serve as a mentor and support the career development of Dr. Xiaowu Pang, a basic science researcher at Howard University with great potential in translational cancer research. To pursue this goal, Dr. Xiaowu Pang will focus on three areas during the funding period: 1) to develop a solid translational research project in HPV-associated cancer, 2) to enhance research and training opportunities for students from Howard University, and 3) to generate sufficient preliminary data to acquire additional extramural support through traditional NIH/NCI grant applications. The objectives will be actively pursued through a joint research project between Dr. Pang's and Dr. Wu's laboratories focusing on antigen-specific immunotherapy for cancer. Since constant expression of Human papillomavirus (HPV) viral proteins E6 and E7 is required for transformation and maintenance of the malignant phenotype, E6 and E7 antigens may represent ideal targets for therapeutic vaccines against HPV- associated cancer. The efficacy of a therapeutic vaccine can be further enhanced by combination with modulation of the cancer microenvironment, Self-replicating RNA vectors (termed RNA replicons) based on flavivirus have been developed in recent years, and show great potential as vaccine vectors. The replicons are non-cytopathic, induce strong cellular immune responses, and can be incorporated into virus-like particles (VLP) by packaging cell lines. Dengue virus, a mosquito-borne flavivirus, produces strong immune reactions in natural infection. The phenomenon of immune enhancement among four serotypes of dengue viruses may be used to further increase the efficacy of dengue vectors. The specific aims of this pilot project are: 1) To characterize the antigen-specific immune responses following vaccination with a therapeutic HPV-associated cancer vaccine using dengue viral replicon-based vectors. 2) To characterize the antitumor effects against an HPV E6/E7-expressing tumor model following vaccination with the therapeutic dengue viral vector-based vaccine. 3) To characterize the combination immunotherapy with the therapeutic vaccine and tumor microenvironment modulation in a mouse tumor model. These specific aims will support the broader goals of this project to enhance translational research at Howard University through the collaboration with Johns Hopkins Cancer Center.